Kidney + Stem Cell Transplant for Immune Tolerance

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Stanford University

Disqualifiers: Cancer, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if blood stem cells can enable kidney transplant patients to stop taking immunosuppressive drugs. The research uses stem cells and a mild form of radiation (Total Lymphoid Irradiation) to help the body accept a new kidney without long-term medication. Participants must have a healthy, fully HLA-matched sibling willing to donate both a kidney and stem cells. The trial requires participants to stay near Stanford for six weeks after surgery. As a Phase 1 and Phase 2 trial, this research seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that immunosuppressive drugs will be gradually reduced after the transplant, so you might need to adjust your medications during the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that hematopoietic cell transplantation can help the body accept a new kidney safely. Side effects are manageable, particularly with less intense treatments, which patients have tolerated well.

Studies indicate that total lymphoid irradiation is usually well-tolerated with few serious issues. This treatment may protect kidney function after a transplant by slowing common long-term problems. However, long-term safety data remains limited.

These treatments aim to help the immune system accept the new kidney without long-term use of immunosuppressive drugs, potentially reducing risks like infections or other health issues related to those drugs. Discussing specific details and risks with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment because it aims to induce immune tolerance in kidney transplant patients, potentially eliminating the need for lifelong immunosuppressive drugs. Unlike standard treatments that rely on continuous immunosuppression to prevent organ rejection, this approach uses a combination of kidney and hematopoietic stem cell transplantation from a living donor to achieve mixed chimerism. This process enables the recipient's immune system to accept the transplanted kidney as its own, significantly reducing the risk of rejection and the side effects associated with immunosuppressive medications.

What evidence suggests that this trial's treatments could be effective for immune tolerance in kidney transplantation?

In this trial, participants will receive a combination of kidney transplantation and hematopoietic cell transplantation. Research has shown that this combination can help the body accept the new kidney without constant medication. This approach has successfully maintained kidney health for over two years without rejection. Additionally, participants will undergo total lymphoid irradiation, a specific type of radiation therapy, to prepare the body and increase the chances of acceptance. Together, these treatments offer hope that people might stop taking anti-rejection drugs after a kidney transplant. ^{2 4 6 7 8}

Who Is on the Research Team?

Samuel Strober, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for kidney transplant patients at Stanford who have a healthy sibling with matching human leukocyte antigens (HLA). Participants must not have HIV, Hepatitis B or C, low white blood cell or platelet counts, high antibody levels against transplants, a history of cancer (except certain skin cancers), previous organ transplants, or allergies to rabbit proteins. They should agree to use reliable contraception for two years post-transplant.

Inclusion Criteria

I agree to use birth control for at least 24 months after my transplant.

I have a sibling who is a perfect match for a donation.

Kidney transplant performed at Stanford University Medical Center

Exclusion Criteria

I have been treated with rabbit ATG or am allergic to rabbit proteins.

Thrombocytopenia (platelet count less than 100,000/mm³)

My immune system is highly likely to reject a transplanted organ.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4-8 weeks

Pre-Transplant Preparation

Blood stem cells are removed from the donor and frozen; recipients receive radiation and anti-T cell antibody treatments for two weeks

2 weeks

Transplantation and Initial Treatment

Kidney transplantation followed by injection of stem cells; patients receive mycophenolate mofetil for one month and cyclosporine for 6-12 months

6-12 months

Follow-up

Participants are monitored for graft function, chimerism, and immune tolerance; cyclosporine is tapered and potentially discontinued at 6 months

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Hematopoietic Cell Transplantation
• Total Lymphoid Irradiation

Trial Overview The study tests if injecting the patient with their HLA-matched sibling's blood stem cells after kidney transplantation and lymphoid irradiation can eliminate the need for lifelong immunosuppressive drugs. The process involves pre-transplant donor cell collection, post-surgery radiation and anti-T cell treatment before stem cell injection. If successful, drug withdrawal starts six months later.

How Is the Trial Designed?

Group I: Immune tolerance, kidney transplantation Experimental Treatment 2 Interventions

Intervention: Participants will receive hematopoietic cell transplantation and Total lymphoid irradiation. The intervention is intended to induce immune tolerance in HLA-matched living donor kidney transplantation, to allow withdrawal of the immunosuppressive drugs. Immune tolerance is achieved through the development of donor/recipient mixed chimerism following combined kidney and hematopoietic stem cell transplantation from the living donor.

Hematopoietic Cell Transplantation is already approved in European Union for the following indications:

Approved in European Union as Trecondi for:

• Allogeneic haematopoietic stem cell transplantation for malignant and non-malignant diseases

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

In a study involving nine patients, the infusion of donor hematopoietic stem cells after kidney transplantation led to significant changes in protein profiles, suggesting a potential mechanism for inducing immune tolerance and preventing organ rejection.

The analysis revealed that proteins related to inflammation and the complement system were downregulated in patients receiving combined kidney and stem cell transplants, indicating a shift towards a more tolerant immune response compared to those with kidney transplants alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation induces immunologic tolerance in renal transplant patients via modulation of inflammatory and repair processes. Wu, D., Qi, G., Wang, X., et al.[2021]

Busulfan has a well-established role in high-dose chemotherapy for treating hematologic malignancies and has been extensively studied for over 30 years, providing a clear understanding of its efficacy and pharmacokinetics.

Treosulfan, a newer analogue of busulfan, shows promise in treating hematologic malignancies but requires further research to fully understand its complex metabolism and pharmacological activity, particularly its pharmacokinetics and pharmacodynamics in high-dose chemotherapy contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan. Galaup, A., Paci, A.[2013]

Treosulfan, an alkylating agent used for ovarian cancer, effectively depletes primitive hematopoietic stem cells in a dose-dependent manner, similar to busulfan, making it a potential alternative for conditioning before stem cell transplantation.

In a murine model, low-dose treosulfan combined with an immune-suppressive regimen allowed for stable mixed chimerism and donor-specific tolerance without causing graft-versus-host disease, suggesting its utility in nonmyeloablative transplantation protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of treosulfan to a nonmyeloablative conditioning regimen results in enhanced chimerism and immunologic tolerance in an experimental allogeneic bone marrow transplant model. Ploemacher, RE., Johnson, KW., Rombouts, EJ., et al.[2013]

In a multicenter trial involving 56 patients with hematologic malignancies, treosulfan was safely administered as a conditioning agent for stem-cell transplantation, with no cases of engraftment failure and low nonrelapse mortality (20%) over 2 years.

The study found that treosulfan at a dose of 14 g/m² showed promising results, combining low toxicity with a lower incidence of relapse, making it a candidate for further research in conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning. Casper, J., Wolff, D., Knauf, W., et al.[2019]

Tr1 cell-enriched lymphocytes can be generated from patients on dialysis awaiting kidney transplantation, but using total peripheral blood mononuclear cells (PBMCs) resulted in a low anergic phenotype, making them unsuitable for clinical use.

In contrast, using purified CD4(+) T cells from these patients produced a highly anergic donor-specific product, indicating that tailoring the generation protocol to the patients' immune profiles can enhance the efficacy of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of Donor-specific T Regulatory Type 1 Cells From Patients on Dialysis for Cell Therapy After Kidney Transplantation. Petrelli, A., Tresoldi, E., Mfarrej, BG., et al.[2015]

Injecting donor-derived CD34+ bone marrow stem cells into kidney transplant recipients can help induce tolerance, which is a key goal in transplantation.

In a clinical trial, the infusion of these cells was found to be safe and well tolerated, with no adverse effects reported, highlighting their potential for improving transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infusion of donor-derived hematopoietic stem cells in organ transplantation: clinical data. De Pauw, L., Toungouz, M., Goldman, M.[2004]

Treosulfan, used in combination with fludarabine, shows a favorable toxicity profile and effective engraftment in allogeneic hematopoietic stem cell transplantation (SCT), with non-relapse mortality rates between 9-28%.

The regimen demonstrates low relapse rates (5-30%) and promising survival outcomes (40-80%), particularly in patients with myelodysplastic syndrome (36-70% survival) and leukemia in remission (60-70% survival), indicating its potential as a safer alternative to standard conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. Danylesko, I., Shimoni, A., Nagler, A.[2013]

A radiation-free conditioning regimen using Treosulfan successfully induced permanent mixed multilineage chimerism and donor-specific tolerance in recipient mice, demonstrating its potential for safer transplantation protocols.

Treosulfan showed lower nonhematological toxicity compared to traditional myeloablative treatments like irradiation or busulfan, making it a promising candidate for conditioning in organ transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards a myeloablative regimen with clinical potential: I. Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers. van Pel, M., van Breugel, DW., Vos, W., et al.[2013]

Treosulfan demonstrated significant antileukaemic activity in pediatric models of acute lymphoblastic leukaemia (ALL), achieving complete regression of tumors and long-term survival in treated mice, outperforming equitoxic doses of busulfan and cyclophosphamide.

While treosulfan caused some myelotoxicity and minor weight loss, these side effects were manageable, suggesting it could be a promising alternative conditioning agent for stem cell transplantation in patients with hematological malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antileukaemic activity of treosulfan in xenografted human acute lymphoblastic leukaemias (ALL). Fichtner, I., Becker, M., Baumgart, J.[2019]

Citations

1. withpower.com withpower.com/trial/phase-1-8-2018-57809

Hematopoietic Cell Transplantation for Immune Tolerance ... Treosulfan has shown effectiveness in creating immune tolerance and stable donor cell integration in bone marrow transplant models, which suggests it could ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0955470X23000460

Review article Hematopoietic cell-based and non- ... The purpose of this paper is to review the safety and efficacy of immune tolerance induction strategies in living-donor kidney transplantation, both chimerism- ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3507650/

Hematopoietic stem cell transplantation induces immunologic ... The induction of immune tolerance has the potential to prevent this chronic rejection and drug toxicity. Immune tolerance of organ transplants ...

4. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.796456/full

Successful Induction of Specific Immunological Tolerance ... Successful induction of specific immunological tolerance by combined kidney and hematopoietic stem cell transplantation in HLA-Identical Siblings.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1600613525000735

Induction of immune tolerance in living related human ... Kidney transplant recipients receiving MDR-101 achieved donor mixed chimerism and functional immune tolerance for greater than 2 years with no death, graft loss ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7723571/

Tolerance induction with donor hematopoietic stem cell ... Immunosuppressive therapy after life-saving kidney transplantation increases the risk of infection, cardiovascular diseases, metabolic diseases, and cancer.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2723946/

Hematopoietic Cell Transplantation for Tolerance Induction Clinical safety data obtained with the above non-myeloablative HCT protocols provided an opportunity to attempt to induce transplantation tolerance in patients ...

8. academic.oup.com academic.oup.com/ecco-jcc/article/19/Supplement_1/i9/7966941

outcomes from the international stem cell transplant consortium 65% of patients were in clinical remission. 46% did not require advanced therapy following HSCT and of patients that started an advanced therapy ...